The interactions between prostate cancer cells and the bone stroma facilitate the progression of metastases growing in bone and bone marrow. Understanding the bone stromal microenvironment and its postive impact on growth of prostate cancer cells at both cellular and molecular levels will allow us to develop novel therapeutic strategies specifically targeted to bone metastases. Heparin/heparan sulfate binding growth factors (HBGF) produced by bone marrow, by prostate cancer cells themselves, and sequestered in the bone matrix stimulate growth of metastatic prostate cancer cells. Agents that disrupt interactions between prostate cancer cells and the bone environment are expected to reduce the growth of metastatic prostate cancer cells at bony sites. Our hypothesis is that heparan sulfate proteoglycans in the stromal extracellular matrix, the most abundant of which is perlecan, function as co-receptors to deliver heparin binding growth factors to prostate cancer cell HB growth factor receptors. Three overall specific aims are proposed to test this hypothesis and to dissect the complex HBGF-mediated paracrine actions occurring between marrow stromal cells and prostate cancer cells. These studies will take advantage of prior work in our laboratory that has generated powerful reagents for disrupting HBGF-dependent signaling. Specifically, two types of interventions, a heparin binding protein (HIP) and related bioactive peptide and a perlecan ribozyme that we have generated will be tested for the ability to interfere with HBGF stimulation of prostate cancer cell growth. Strong preliminary studies indicate that PIn knockdown by an active ribozyme inhibits growth of prostate cancer cells in a mouse model. Together, our studies will complement other projects in the program project focusing on the important role of the stromal-epithelial interactions supporting prostate cancer progression. Finally, this project will support the training of a ribozyme core technician who will work with us in Delaware but who will be responsible for production of functional ribozymes as needed for other projects in the program.